Dnmt2 mediates intergenerational transmission of paternally acquired metabolic disorders through sperm small non-coding RNAs

• Published in: Nature cell biology Vol. 20; no. 5; pp. 535 - 540
• Main Authors: Zhang, Yunfang, Zhang, Xudong, Shi, Junchao, Tuorto, Francesca, Li, Xin, Liu, Yusheng, Liebers, Reinhard, Zhang, Liwen, Qu, Yongcun, Qian, Jingjing, Pahima, Maya, Liu, Ying, Yan, Menghong, Cao, Zhonghong, Lei, Xiaohua, Cao, Yujing, Peng, Hongying, Liu, Shichao, Wang, Yue, Zheng, Huili, Woolsey, Rebekah, Quilici, David, Zhai, Qiwei, Li, Lei, Zhou, Tong, Yan, Wei, Lyko, Frank, Zhang, Ying, Zhou, Qi, Duan, Enkui, Chen, Qi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2018; Nature Publishing Group
• Subjects: 13/109; 38/71; 38/77; 38/90; 38/91; 45/29; 59; 631/337/1645/2570; 631/337/384/521; 631/443/319/1642/393; 631/532/2442; 64; 64/60; 82/58; Animals; Biological properties; Biomarkers - blood; Biomedical and Life Sciences; Blood Glucose - metabolism; Cancer Research; Cell Biology; Developmental Biology; Diet; Diet, High-Fat; Disorders; DNA (Cytosine-5-)-Methyltransferases - deficiency; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA (Cytosine-5-)-Methyltransferases - metabolism; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Gene expression; Gene Expression Regulation, Developmental; Gene-Environment Interaction; Genetic Predisposition to Disease; Glucose Metabolism Disorders - blood; Glucose Metabolism Disorders - diagnosis; Glucose Metabolism Disorders - enzymology; Glucose Metabolism Disorders - genetics; Heredity; High fat diet; Insulin - blood; Letter; Life Sciences; Male; Metabolic disorders; Methyltransferases; Mice; Mice, Inbred C57BL; Mice, Knockout; NIH 3T3 Cells; Nucleic Acid Conformation; Offspring; Paternal Inheritance; Phenotype; Phenotypes; Protein structure; Ribonucleic acid; RNA; RNA, Small Untranslated - chemistry; RNA, Small Untranslated - genetics; RNA, Small Untranslated - metabolism; rRNA; Secondary structure; Sperm; Spermatozoa - enzymology; Stem Cells; Structure-Activity Relationship; Transcriptome; Transfer RNA; Transferases; tRNA; tRNA methyltransferase
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/s41556-018-0087-2

The discovery of RNAs (for example, messenger RNAs, non-coding RNAs) in sperm has opened the possibility that sperm may function by delivering additional paternal information aside from solely providing the DNA 1 . Increasing evidence now suggests that sperm small non-coding RNAs (sncRNAs) can mediate intergenerational transmission of paternally acquired phenotypes, including mental stress 2 , 3 and metabolic disorders 4 – 6 . How sperm sncRNAs encode paternal information remains unclear, but the mechanism may involve RNA modifications. Here we show that deletion of a mouse tRNA methyltransferase, DNMT2, abolished sperm sncRNA-mediated transmission of high-fat-diet-induced metabolic disorders to offspring. Dnmt2 deletion prevented the elevation of RNA modifications (m 5 C, m 2 G) in sperm 30–40 nt RNA fractions that are induced by a high-fat diet. Also, Dnmt2 deletion altered the sperm small RNA expression profile, including levels of tRNA-derived small RNAs and rRNA-derived small RNAs, which might be essential in composing a sperm RNA ‘coding signature’ that is needed for paternal epigenetic memory. Finally, we show that Dnmt2-mediated m 5 C contributes to the secondary structure and biological properties of sncRNAs, implicating sperm RNA modifications as an additional layer of paternal hereditary information. Zhang et al. report that tRNA methyltransferase Dnmt2 is required for sperm small-non-coding-RNA-mediated transmission of paternal metabolic disorders to the offspring.